A quantum mechanical/molecular mechanical (QM/MM) approach based on an approximate density functional theory, the so-called self-consistent charge density functional tight binding (SCC-DFTB) method, has been implemented in the CHARMM program and tested on a number of systems of biological interest. In the gas phase, SCC-DFTB gives reliable energetics for models of the triosephosphate isomerase (TIM) catalyzed reactions. The rms errors in the energetics compared to B3LYP/6-31+G(d,p) are about 2-4 kcal/mol; this is to be contrasted with AM1, where the corresponding errors are 9-11 kcal/mol. The method also gives accurate vibrational frequencies. For the TIM reactions in the presence of the enzyme, the overall SCC-DFTB/CHARMM results are in somewhat worse agreement with the B3LYP/6-31+G(d,p)/CHARMM values; the rms error in the energies is 5.3 kcal/mol. Single-point B3LYP/CHARMM energies at the SCC-DFTB/CHARMM optimized structures were found to be very similar to the full B3LYP/CHARMM values. The relative stabilities of the alpha (R) and 3(10) conformations of penta- and octaalanine peptides were studied with minimization and molecular dynamics simulations in vacuum and in solution. Although CHARMM and SCC-DFTB give qualitative different results in the gas phase (the latter is in approximate agreement with previous B3LYP calculations), similar behavior was found in aqueous solution simulations with CHARMM and SCC-DFTB/CHARMM. The 310 conformation was not found to be stable, and converted to the alpha (R) form in about 15 ps. The cia conformation was stable in the simulation with both SCC-DFTB/CHARMM and CHARMM. The i,i+3 CO HN distances in the CIR conformation were shorter with the SCC-DFTB method (2.58 Angstrom) than with CHARMM (3.13 Angstrom). With SCC-DFTB/CHARMM, significant populations with i,i+3 CO.. HN distances near 2.25 Angstrom, particularly for the residues at the termini, were found. This can be related to the conclusion from NMR spectroscopy that the 310 configuration contributes for alanine rich peptides, especially at the termini.